MYC (v-myc myelocytomatosis viral oncogene homolog) is a pleiotropic transcription factor that regulates a variety of functions by promoting activation or repression of genes on a global scale, and plays a central role in the pathophysiology of cancer, inflammation, and heart disease.
The overexpression of MYC is common in many types of human cancer. Tumors can employ multiple genetic and epigenetic mechanisms to upregulate MYC, and such amplification or overexpression is often correlated with a poor clinical outcome, aggressive biological behavior, increased likelihood of relapse, and advanced stage of disease (Gamberi G., et al., Oncology. 1998; 55:556-563; Nesbit C. E., et al, Oncogene. 1999; 18:3004-3016). Recently, MYC expression in tumor cells has also been shown to regulate the tumor microenvironment through effects on both innate and adaptive immune effector cells and immune regulatory cytokines, and MYC inactivation can restore the immune response against a tumor (Casey, S. C., et al., Blood. 2018; 131(18):2007-2015). Beyond cancer, MYC gene is frequently deregulated in tissue inflammation, and its overexpression or activation has been observed in both sporadic and colitis-associated colon adenocarcinomas and in disease conditions such as rheumatoid arthritis (Sipos, F., et al., World Journal of Gastroenterology. 2016; 22(35):7938-7950; Pap, T., et al., Arthritis Rheum. 2004; 50:2794-2802). MYC function has also been implicated in the pathophysiology of heart failure during tissue remodeling associated with hypertrophy and, dilatation (Ahuja, P., et al., J Clin Invest. 2010; 120:1494-1505). Thus, MYC is an appealing target for discovery and development of therapeutics. To date, despite unmet medical needs, small molecule inhibitors of MYC have remained elusive, and MYC has thus far proven undruggable (Prochownik, E. V., et al., Genes Cancer. 2010; 1(6):650-659; Nair, S. K., et al., Cell. 2003; 112:193-205).
Increasing evidence suggests that targeting upstream MYC regulators may be an effective strategy to suppress MYC. One of such strategies is to inhibit bromo and extra-terminal (BET) bromodomain proteins such as bromodomain-containing protein 4 (BRD4), which are transcriptional regulators that are required for the efficient expression of MYC (Delmore, J. E., et al, Cell 2011; 146(6):904-917; Mertz, J. A., et al, Proc Natl Aced Sci USA. 2011; 108:16669-16674; Puissant, A., Cancer Discov. 2013; 3(3):308-323). The bromodomain (BRD) family of proteins is a class of epigenetic readers that recognize acetyllysine (KAc) residues of histones. The binding interaction between BRDs and histories creates a scaffold for the assembly of protein complexes that alter chromatin accessibility to transcription factors and allows the recruitment or activation of RNA polymerases, leading to regulation of gene transcription and/or chromatin remodeling. BET bromodomain inhibition exerts a broad spectrum of desired biological effects such as anticancer, anti-inflammatory properties. BRD4 is ubiquitously expressed and contains two highly conserved N-terminal bromodomains (BD1 and BD2), an ET domain, and a C-terminal domain. BRD4 (BD1) and BRD4 (BD2) interact with acetylated chromatin as well as nonhistone proteins to regulate transcription, DNA replication, cell cycle progression, and other cellular activities (Wu, S. Y., et al., J Bio Chem. 2007; 282:13141-13145). Most BRD4 inhibitors block the interactions between BRD4 and acetyl-lysine by mimicking acetyl-lysine and competing with it to bind BRD4.
Targeting MYC function via BET bromodomain inhibition has now been validated by studies in Burkitt lymphoma, B- and T-cell acute lymphoblastic leukemia, non-small-cell lung carcinoma, diffuse large B-cell lymphoma, and neuroblastoma (Filippakopoulos, P., et al., Nature. 2010; 468(7327)1067-1073; Zhang, G., et al, Chem Rev. 2015; 115(21):11625-11668; Delmore J. E., et al., Cell. 2011; 146(6):904-917; Dawson, M. A., et al., Nature. 2011; 478:529-533; Puissant, A., et al., Cancer Discov. 2013; 3(3):308-323; Ran, X., et al., J Med Chem. 2015; 58(12):4927-4939; Zhang, a, et al., J Med Chem. 2013; 56(22):9251-9264; Zhao, L., et al., J Med Chem. 2015: 58(3)1281-1297; Picaud, S., et al., Cancer Res. 2015; 75(23):5106-5119). To date, at least seven BET bromodomain inhibitors are in active clinical trials for cancer (Andrieu, G., et al., Drug Discovery Today: Technol. 2016; 19:45-50), but none has received FDA approval.
Although BET bromodomain inhibitors show great promise as cancer therapeutics, emerging studies have shown that cancer cells can acquire resistance to inhibition of BET bromodomain, indicating that single-agent therapies targeting BRD4 may not provide durable therapeutic response. Resistance to BET bromodomain inhibitors is mediated by adaptive kinome reprogramming, and co-targeting BET bromodomain proteins and receptor tyrosine kinases (RTKs) and/or phosphatidylinositol 3-kinase (PI3K) signaling may be required to maximize clinical benefit (Kurimchak, A. M., et al., Cell Reports. 2016; 16:1273-1286).
The PI3K signaling pathway, defined by PI3K, AKT (serine/threonine kinase) and mTOR (mammalian target of rapamycin), is one of the key signaling networks in cancer cell initiation, growth, proliferation, and survival (Engelman, J. A., et al., Nat Rev Genet. 2006; 7(8):606-619; Liu, P., et al., Nat Rev Drug Discov. 2009; 8(8):627-644). Blockade of the PI3K pathway has also been shown to suppress MYC activity by inhibiting MYC gene transcription (Dey, N., et al., Am J Cancer Res. 2015; 5:1-19) and decreasing MYC protein stability, and PI3K inhibition potentiates MYC down-regulation and cell death in MYC-dependent NMC cells (Tinsley, S., et al., Br J Haematol. 2015; 170;275-278).
The main PI3-kinase isoforms in cancer are class I PI3Ks, designated PI3K α, β, δ, and γ, each comprising a 110 kDa catalytic subunit and a smaller associated regulatory subunit. Class Ia PI3Ks (α, β, and δ) containing the catalytic subunits p110α, p110β, and p110δ, respectively, are activated through tyrosine kinase signaling. In contrast, the sole class Ib member, PI3Kγ, contains catalytic subunit p110γ associated with either a p101 or p84 regulatory subunit, and is mostly activated through GPCRs. While PI3Kα and PI3Kβ are ubiquitously expressed, and the dysregulation of PI3Kα and PI3Kβ is implicated in the etiology of solid tumors. PI3Kδ and PI3Kγ are found in leukocytes (B and T cells, and myeloid lineage cells) with PI3Kδ nearly confined to spleen, thymus, and peripheral blood leukocytes (Eickholt, B. J., et al., PLoS One. 2007; 2(9):e869; Kok, K., et al., Trends Biochem. Sci. 2009; 34:115-127), and the dysregulation of P13 .6 and PI3Kγ has been implicated in diseases of the innate and, adaptive immune system such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and hematological malignancies. PI3Kγ inhibition breaks the regulatory checkpoint in T cells in a wide range of solid tumours, and the blockade of PI3Kγ in myeloid cells suppress inflammation, growth and metastasis of tumours (Ali, K., et al., Nature. 2014; 510:407-411; Schmid, M. C., et al., Cancer Cell. 2011; 19:715-727); however, like immune checkpoint inhibitors, idelalisib, the first p110δ-selective inhibitor approved by FDA, has immune-related toxicity in the gastrointestinal tract (Weidner, A-S., et al., Am J Surg Pathol. 2015; 39:1661-1667).
Abundant evidence has also revealed that the PI3K pathway is, frequently mutated or altered in numerous forms of human cancers (e.g., breast tumors), and emerging clinical data show limited single-agent activity of over 30 clinical candidates targeting, the PI3K pathway at tolerated doses in solid tumors with an accompanied rapid emergence of drug resistance (Liu, P., et al., Nat Rev Drug Discov. 2009; 8(8):627-644; https://clinicaltrials.gov/; Dey, N., et al., Am J Cancer Res. 2015; 5(1):1-19; Fruman, D. A., et al., Nat Rev Drug Discov. 2014; 13(2):140-156). It is clear that there is an unmet need for novel second-generation PI3K inhibitors with improved efficacy and more durable responses over existing drugs in order to overcome the limitation of PI3K inhibition in the treatment of heterogeneous and drug-resistant tumors; there is also an unmet need for developing more efficacious drugs with improved tolerability to treat MYC-driven and PI3K-related cancer.
It is evidenced that PI3Ks and MYC form interlinked but overlapping signaling pathways (Gang, C. V., Cell. 2012; 149(1):22-35). Both pathways are often dysregulated cooperatively in hematopoietic malignancies, and in patients with Burkitt lymphoma as well as in a mouse model of the disease (Sander, S., et al., Cancer Cell. 2012; 22(2):167-179; Schmitz, R., et al., Nature. 2012; 490:116-120). MYC upregulation can impair the response to PI3K inhibitors and is an important mechanism underlying tumor resistance to PI3K pathway inhibition (Klempner, S. J., et al., Cancer Discovery. 2013; 3:1345-1354; Shepherd, C., et al., Leukemia. 2013; 27(3):650-660). Recently, drug-based perturbation screen uncovers that idelalisib was synergistic when combined with BET inhibitors such as JQ1 and OTX015, and, more importantly, synergy for OTX015 with idelalisib at concentrations in vitro observed can be safely administrated in the clinical setting in vivo (Tomska, K., et al., Scientific Reports. 2018; 8:12046). Thus, co-targeting both PI3K and BRD4 could be a rational and sensible combination strategy.
The “multi-targeted or dual-targeted single agent” therapeutic strategy is well-established and, in principle, could confer the same benefits as combination therapies without major clinical development challenges and high treatment costs (Talevi, A., Front Pharmacol. 2015; 6:205). To date, many multitarget drugs have been approved or are in advanced development stages, and many dual kinase-bromodomain inhibitors have been identified from known kinase inhibitors (Xiao, H. M., <et al., Pharm Res. 2010; 27:739-749; Ciceri, P., et al., Nat'Chem Biol. 2014; 10(4):305-312; Ember, S. W., et al., ACS Chem Biol. 2014; 9(5):1160-1171). However, dual PI3-kinase and bromodomain inhibitors are rare (Dittmann, A., et al., ACS Chem. Biol. 2014; 9(2):495-502; US 20150315207/US 20170101418). A dual inhibitor of PI3K-BRD4 blocks cancer cell growth and metastasis via the orthogonal inhibition of MYC, and is less toxic to the host organism in vivo than a combination of an equipotent PI3K inhibitor and BRD4 inhibitor (Andrews, F. H., et al., Proc Natl Acad Sci USA. 2017; 114(7):E1072-E1080).
It is clear that there is an unmet need for therapeutically effective inhibitors with improved tolerability over existing drugs, there is an unmet need for small molecules co-targeting both PI3K signaling pathway and bromodomain proteins such as BRD4. The present invention provides such compounds as further described below.